The first (and so far, only) chimeric antigen receptor T-cell (CAR-T) therapies—Kymriah (Novartis; Basel, Switzerland) and Yescarta—(Gilead; Foster City, CA) were approved in 2017, and remain one of the hottest immunotherapies on the market today. They work by boosting the body’s ability to recognize and attack cancer cells. This WEEKLY reviews the basics of CAR-T technology. Next week, we’ll take a peek at CAR-T innovations moving through the pipeline.

TERM OF THE WEEK: KILLER T-CELLS

CAR-T therapy is based on a type of white blood cell called a killer T-cell. The job of these cells is exactly what the name implies—to kill dangerous cells. They target diseased cells in the body via cell-surface receptors: each has a uniquely shaped receptor, and recognizes its intended target because the shape of its receptor “matches” or fits into a uniquely-shaped surface protein found only on diseased cells. Once the killer T-cell “docks” onto its target, it injects an enzyme which triggers death. The result: no more bad cells.

killer-t-cells-in-action

WHY CAR-T?

In theory, our immune system should recognize the unique proteins presented on cancerous cells. However, there are two main reasons this doesn’t always happen:

  1. Early on in the tumor development, the cell composition is similar enough to healthy tissue that it can be overlooked by the immune system.

2. Later, as a tumor progresses, it releases chemical signals that suppress the immune response, helping it to evade detection. This trickery is known as the tumor microenvironment and once again the dangerous cancer cells can pass by undetected.

So what’s a scientist to do?!  Figure out a way to train killer T-cells to ALWAYS recognize and destroy cancer cells…enter CAR-T.

HOW TO TRAIN AN IMMUNE SYSTEM

CAR-T therapies boost the body’s ability to recognize and attack cancer cells. These “super” killer T-cells have been physically enhanced to go after cancer. Like the mythical chimera, this drug is composed of different parts. Genetic engineers fuse an antibody with a killer T-cell receptor to create a chimeric molecule—the “C” in CAR-T.

The transformation begins with technicians removing killer T-cells from a patient’s body and isolating them in the lab. Next, scientists use a viral vector—a virus that has been modified to contain a therapeutic gene—to deliver a gene that encodes the chimeric receptor to the T-cells.

The enhanced receptor includes two parts: a targeting domain and an activation domain. The first is the portion that remains on the surface of the T-cell. It’s an antibody that detects and locks onto a specific surface protein on the patient’s malignant cells. The activation domain part of the receptor is triggered once the targeting domain attaches itself to the desired cancer protein.

The engineered T-cells are then reinfused into the patient.

Once back inside the patient, the targeting domain finds the proper surface protein on the tumor cell and attaches to it. Then, the activation domain signals the killer T-cell to:

  • Stay alive.
  • Make copies of itself (replicate).
  • Release cytokines—chemical signals that activate other white blood cells to assault the tumor.
  • Kill the target cell.

WHAT’S IN A NAME?

Chimeric antigen receptor therapy broken down:

  • Chimeric: Composed of components from two distinct parts, such as an antibody and a killer T-cell receptor.
  • Antigen: A protein that is recognized by an antibody, such as a protein on the surface of a tumor cell.
  • Receptor: A protein that is embedded in a cell membrane and transmits signals to itself in response to being activated, for example a T-cell receptor transmits signals to the T-cell when it docks onto its target.
  • T-Cell: A white blood cell that kills harmful cells.  (Article continues below)

Immunotherapy, Cell Therapy, and Gene Therapy Oh My!

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Tricky Terminology

The medical community classifies CAR-Ts as a “cell-based gene therapy.” They’re immune cells that have been engineered using gene therapy techniques.

In The Pipeline

Two CAR-T therapies have currently been approved, several more are in clinical development. The table below shows a selection of CAR-T therapies moving through the clinic:

Biopharma never rests. Industry scientists are busy creating the next generation of CAR-T therapies, which should prove to be both safer and more effective than the first generation. Tune in next week as we discuss these new therapies.

Co Authors :

Sarah Van Tiem

Editor

Sarah Van Tiem began her career with Detroit Legal News, gaining unparalleled experience in public communication. Subsequent stints at Earthwatch Radio and Wisconsin Department of Natural Resources established Sarah as a respected writer/editor. Currently working as Editor for the Biotech Primer WEEKLY newsletter, Sarah is widely known for her expertise in science communication.

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